Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was shown to be clinically active and tolerable in patients with advanced urothelial carcinoma and prespecified ...FGFR alterations in the primary analysis of the BLC2001 study at median 11 months of follow-up. We aimed to assess the long-term efficacy and safety of the selected regimen of erdafitinib determined in the initial part of the study.
The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America. Eligible patients were aged 18 years or older with locally advanced and unresectable or metastatic urothelial carcinoma, at least one prespecified FGFR alteration, an Eastern Cooperative Oncology Group performance status of 0–2, and progressive disease after receiving at least one systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were ineligible for cisplatin. The selected regimen determined in the initial part of the study was continuous once daily 8 mg/day oral erdafitinib in 28-day cycles, with provision for pharmacodynamically guided uptitration to 9 mg/day (8 mg/day UpT). The primary endpoint was investigator-assessed confirmed objective response rate according to Response Evaluation Criteria In Solid Tumors version 1.1. Efficacy and safety were analysed in all treated patients who received at least one dose of erdafitinib. This is the final analysis of this study. This study is registered with ClinicalTrials.gov, NCT02365597.
Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen. The data cutoff date for this analysis was Aug 9, 2019. Median efficacy follow-up was 24·0 months (IQR 22·7–26·6). The investigator-assessed objective response rate for patients treated with the selected erdafitinib regimen was 40 (40%; 95% CI 30–49) of 101 patients. The safety profile remained similar to that in the primary analysis, with no new safety signals reported with longer follow-up. Grade 3–4 treatment-emergent adverse events of any causality occurred in 72 (71%) of 101 patients. The most common grade 3–4 treatment-emergent adverse events of any cause were stomatitis (in 14 14% of 101 patients) and hyponatraemia (in 11 11%). There were no treatment-related deaths.
With longer follow-up, treatment with the selected regimen of erdafitinib showed consistent activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations.
Janssen Research & Development.
The mammalian target of rapamycin (mTOR) pathway inhibitors are key drugs for the treatment of many tumor types, however, there are no predictive biomarkers in clinical use. Here, we performed a ...molecular and immunohistochemical characterization of key mTOR pathway components in a series of 105 renal cell carcinoma patients treated with rapalogs, aimed at identifying markers of treatment response. Mutational analysis in MTOR, TSC1 and TSC2 was performed through targeted next‐generation sequencing (NGS), and immunohistochemistry (IHC) was performed for PTEN, pAKT, pS6K1, pS6 and p21. Among patients with NGS data, 11 of 87 (13%) had mTOR pathway mutations (8 in MTOR, 1 in TSC1 and 2 in TSC2). When comparing the molecular data to the response of the patients, we found that partial response was more frequent in cases with mTOR pathway mutations than in those without mutations (odds ratio OR = 0.08, 95% confidence interval CI = 0.008–0.79, p = 0.030 univariate; p = 0.038 multivariable). Regarding IHC, negative PTEN staining was detected in 58% of the tumors, and it was more frequent in rapalog responder patients (OR = 0.24, 95% CI = 0.065–0.86, p = 0.029 univariate; p = 0.029 multivariable). Mutations and PTEN IHC were not mutually exclusive events and its combination improved response prediction (OR = 0.16, 95% CI = 0.04–0.62, p = 0.008 univariate; p = 0.013 multivariable). The staining of other proteins did not show and association with response and no association with PFS was observed in unselected patients. In conclusion, our findings suggest that mTOR pathway mutations, negative PTEN IHC and their combination are potential markers of rapalog response.
What's new?
Inhibitors of the mammalian Target of Rapamycin (mTOR) are key drugs for the treatment of renal cell carcinoma. However, only a subset of patients benefits clinically, and it is unclear why. Here the authors identified mutations in mTOR pathway, as well as loss of expression of the tumor suppressor PTEN, as markers of favorable outcome, underscoring the potential of these markers– either alone or in combination – to serve as clinical tools for patient stratification.
Chromophobe renal cell carcinoma (chRCC) is a histologically and molecularly distinct class of rare renal tumor. TCGA studies revealed low mutational burden, with only TP53 and PTEN recurrently ...mutated, and discovered alterations in TERT promoter and in the electron transport chain Complex I genes. However, knowledge on drug targetable genes is limited and treatments at metastatic stage do not follow a molecular rationale. In a large series of 92 chRCC enriched with metastatic cases, we performed an in-depth characterization of mTOR pathway alterations through targeted NGS and immunohistochemistry (IHC) of phospho-S6, tuberin, and PTEN. Mutations in mitochondria, telomere maintenance and other renal cancer related genes and p53 IHC, were also assessed. The impact on metastasis development and disease specific survival was determined, using TCGA-KICH series (n = 65) for validation. mTOR pathway mutations (MTOR, TSC1, TSC2) were present in 17% of primary tumors, most of them being classified as pathogenic. Mutations were associated with positive IHC staining of phospho-S6 and PTEN (P = 0.009 and P = 0.001, respectively) and with chRCC eosinophilic variant (P = 0.039), supporting a biological relevance of the pathway. mTOR pathway mutations were associated with worse clinical outcomes. Survival analysis gave a hazard ratio of 5.5 (P = 0.027), and this association was confirmed in TCGA-KICH (HR = 10.3, P = 0.006). TP53 mutations were enriched in metastatic cases (P = 0.018), and mutations in telomere maintenance genes showed a trend in the same direction. p53 IHC staining pattern was associated with the underlying TP53 defect, and negative PTEN IHC staining (82% of cases) suggested PTEN loss as a chRCC hallmark. In conclusion, our study provides with novel genomic knowledge in chRCC and identifies novel markers of poor survival. Furthermore, this is the first study showing that mTOR pathway mutations correlate with poor prognosis, and may help to identify patients with increased sensitivity to mTOR inhibitors.
The poly(ADP-ribose) polymerase inhibitor rucaparib is approved as monotherapy in the treatment and maintenance settings for women with relapsed ovarian cancer in the European Union and the United ...States. We review the safety profile of rucaparib in both settings and provide recommendations for the clinical management of the main adverse events (AEs) that may occur during rucaparib treatment. We searched PubMed and congress proceedings for safety data on oral rucaparib monotherapy (600 mg twice daily) from clinical trials involving patients with relapsed ovarian cancer. AE management guidance was developed from clinical trial protocols, rucaparib prescribing information, oncology association guidelines, and author experience. The most frequent any-grade treatment-emergent AEs (TEAEs) included gastrointestinal symptoms, asthenia/fatigue, dysgeusia, anemia/decreased hemoglobin, and increased alanine/aspartate aminotransferase. Across clinical trials, 61.8% of patients had one or more grade 3 or higher TEAEs. Clinicians should employ close follow-up for TEAEs, particularly early in treatment, and educate patients about expected TEAEs and methods for their monitoring and management (e.g., antiemetics for nausea/vomiting, transfusions for hematologic TEAEs, or dose interruptions/reductions for moderate/severe TEAEs). Overall, 16.2% of patients discontinued rucaparib due to TEAEs. Management of AEs that may occur during rucaparib treatment is crucial for patients to obtain optimal clinical benefit by remaining on therapy and to avoid their detrimental impact on quality of life.
Germline pathogenic variants are estimated to affect 3–5% of renal cell carcinoma (RCC) patients. However, higher mutational prevalence in non–clear cell RCC (non-ccRCC) and advanced disease has been ...suggested.
To clarify the prevalence of pathogenic germline variants in metastatic RCC, we sequenced 29 cancer susceptibility genes in 294 unselected metastatic RCC cases plus 21 patients with clinical hereditary features. In 145 tumors, genes frequently mutated in RCC were sequenced and methylation was assessed in selected cases.
Germline variants in RCC predisposition genes (FH, VHL) were detected in 1.4% of the unselected metastatic patients, with higher frequency in non-ccRCC versus ccRCC (6.4% and 0.4%; P = 0.0025) and in younger patients (P = 0.036). Among the 315 studied patients, 14% of non–type 1 papillary cases (4 of 28), all metastatic <1 year after diagnosis, carried a FH germline variant with loss of heterozygosity and tumor genome hypermethylation. Variants in other cancer-associated genes (e.g., MUTYH, BRCA2, CHEK2) occurred in 5.1% of the unselected series, with unclear significance for RCC.
Our findings confirm a high prevalence of pathogenic germline variants in RCC predisposition genes in metastatic non-ccRCC, and highlight that metastatic patients with papillary type 2 or unconventional histologies compatible with FH would benefit from genetic screening.
Clear-cell renal cell carcinomas (ccRCC) can be divided into four transcriptomic subtypes, two of which have a favorable and two an unfavorable prognosis. To assess mechanisms driving these subtypes, ...we investigated their miRNA expression patterns. miRNAs are master regulators of mRNAs, that are widely deregulated in cancer. Unsupervised clustering in our dataset (n = 128) and The Cancer Genome Atlas (TCGA) validation set identified two distinct miRNA clusters that overlapped with the transcriptomic subtypes, underscoring the validity of these subtypes on a multi-omics level and suggesting a driving role for miRNAs. Discriminatory miRNAs for the favorable subtypes repressed epithelial-to-mesenchymal transition, based on gene set enrichment analysis and target-mRNA expression levels. Strikingly, throughout the entire dataset, miRNAs associated with favorable subtypes were also associated with longer overall survival after diagnosis, and miRNAs associated with unfavorable subtypes with shorter overall survival (Pearson r = -0.54, p<0.0001). These findings indicate a general shift in miRNA expression between more and less aggressive tumors. This adds to current literature, which usually suggests only a small subset of miRNAs as markers of aggressive disease. In conclusion, this study reveals distinct mRNA expression patterns underlying transcriptomic ccRCC-subtypes, whereby miRNAs associated with favorable subtypes counteract epithelial-to-mesenchymal transition. There is a general shift in miRNA expression in ccRCC, between more and less aggressive tumors.
Although certain genetic alterations have been defined as predictive and prognostic biomarkers in the context of ovarian cancer (OC), data science methods represent alternative approaches to identify ...novel correlations and define relevant markers in these gynecological tumors. Considering this potential, our work focused both on clinical and genomic data information collected from patients with OC to identify relationships between clinical and genetic factors and disease progression-related variables. For this aim, we proposed two analyses: (1) a nonlinear exploration of an OC dataset using autoencoders, a type of neural network that can be used as a feature extraction tool to represent a dataset in 3-dimensional latent space, so that we could assess whether there are intrinsic or natural nonlinear separability patterns between disease progression groups (in our case, platinum-sensitive and platinum-resistant groups); and (2) the identification of relevant variable relationships by means of an adaptation of the informative variable identifier (IVI), a feature selection method that labels each input feature as informative or noisy with respect to the task at hand, identifies the relationships among features, and builds a ranking of features, allowing us to study which input features and relationships may be most informative for the OC disease progression classification to define new biomarkers involved in disease progression. Our interest has been in clinical and genetic factors and in the combination of clinical features and genetic profile. Results with autoencoders suggest a pattern of separability between disease progression groups in the clinical part and for the combination of genes and clinical features of the OC dataset, that is increased via supervised fine tuning. In the genetic part, this pattern of separability is not observed, but it is more defined when a supervised fine tuning is performed. Results of the IVI-mediated feature selection method show significance for relevant clinical variables (such as type of surgery and neoadjuvant chemotherapy), some mutation genes, and low-risk genetic features. These results highlight the efficacy of the considered approaches to better understand the clinical course of OC.
•Data science methods are suitable for identifying biomarkers in OC.•Feature selection methods show predictive roles of variables in an OC dataset.•Features extraction methods reveal some patterns of separability in an OC dataset.
Background
Peripheral neuropathy is the dose‐limiting toxicity of many oncology drugs, including paclitaxel. There is large interindividual variability in the neuropathy, and several risk factors ...have been proposed; however, many have not been replicated. Here we present a comprehensive study aimed at identifying treatment and physiopathology‐related paclitaxel‐induced neuropathy risk factors in a large cohort of well‐characterized patients.
Patients and Methods
Analyses included 503 patients with breast or ovarian cancer who received paclitaxel treatment. Paclitaxel dose modifications caused by the neuropathy were extracted from medical records and patients self‐reported neuropathy symptoms were collected. Multivariate logistic regression analyses were performed to identify concomitant medications and comorbidities associated with paclitaxel‐induced neuropathy.
Results
Older patients had higher neuropathy: for each increase of 1 year of age, the risk of dose modifications and grade 3 neuropathy increased 4% and 5%, respectively. Cardiovascular drugs increased the risk of paclitaxel dose reductions (odds ratio OR, 2.51; p = .006), with a stronger association for beta‐adrenergic antagonists. The total number of concomitant medications also showed an association with dose modifications (OR, 1.25; p = .012 for each concomitant drug increase). A dose modification predictive model that included the new identified factors gave an area under the curve of 0.74 (p = 1.07 × 10−10). Preexisting nerve compression syndromes seemed to increase neuropathy risk.
Conclusion
Baseline characteristics of the patients, including age and concomitant medications, could be used to identify individuals at high risk of neuropathy, personalizing chemotherapy treatment and reducing the risk of severe neuropathy.
Implications for Practice
Peripheral neuropathy is a common adverse effect of many cancer drugs, including chemotherapeutics, targeted therapies, and immune checkpoint inhibitors. About 40% of survivors of cancer have functional deficits caused by this toxicity, some of them irreversible. Currently, there are no effective treatments to prevent or treat this neuropathy. This study, performed in a large cohort of well‐characterized patients homogenously treated with paclitaxel, identified concomitant medications, comorbidities, and demographic factors associated with peripheral neuropathy. These factors could serve to identify patients at high risk of severe neuropathy for whom alternative non‐neurotoxic alternatives may be considered.
Peripheral neuropathy is a common adverse effect of many cancer drugs, including chemotherapeutics, targeted therapies, and immune checkpoint inhibitors. This article reports results of a study designed to identify treatment and physiopathology‐related paclitaxel‐inducd neuropathy risk factors in a cohort of ore than 500 patients.
To compare the surgical outcome and short-term postoperative complications in premenopausal women who had undergone hysterectomies for benign indication with or without prophylactic bilateral ...salpingectomy.
A cohort of consecutive women who had undergone hysterectomy plus bilateral salpingectomy between May 2012 and July 2014 (group A) were compared with the same number of consecutive premenopausal patients who had undergone simple hysterectomy operated on before May 2012 (group B). Inclusion criteria included premenopausal women and benign indication for surgery (Canadian Task Force classification III).
tertiary care hospital.
Salpingectomy versus no salpingectomy at the time of benign hysterectomy.
A total of 97 and 71 patients were included in groups A and B, respectively. No differences between the 2 groups were observed regarding patient characteristics. The average operative time, estimated blood loss, uterine size, and intraoperative complications were similar between groups. The mean (standard deviation) length of hospitalization time was 43.7 (22.4) hours in group A and 53.9 (83.5) hours in group B (p = .008). There were no significant differences in terms of the incidence of postoperative complications, emergency visits after readmission, and hospital readmission between both groups of patients.
Prophylactic salpingectomy at the time of benign hysterectomy in premenopausal women is safe and feasible and does not worsen surgical outcomes or the incidence of intraoperative and postoperative complications.
PDF
